Elastic fibers are essential extracellular matrix macromolecules comprising an elastin core surrounded by a mantle of fibrillin-rich microfibrils (Kiety et al., J. Cell Sci., 2002 Jul. 15; 115 (Pt 14):2817-28). Elastic fibers provide elasticity and resilience to tissues such as skin and lung. Production of a mature and functional elastic fiber is a complex process because it involves multiple components and requires a tightly regulated deposition and a multi-step hierarchical assembly. Monomers of elastin (tropoelastin) are cross-linked in the extracellular space by one or more members of the lysyl oxidase family to form an elastin polymer, which is the functional form of the mature protein. Fibrillin-containing microfibrils are thought to play an important role in the assembly process by serving as a scaffold for aligning cross-linking domains within tropoelastin.
Lysyl oxidase like-1 (LOXL1) is a member of the lysyl oxidase family which catalyzes the cross-linking of collagen and elastin through oxidative deamination of lysine or hydroxylysine side chains. The resultant allysine residues can spontaneously condense with vicinal peptide aldehydes or with ε-amino groups of peptidyl lysine to generate covalent cross-linkages (Lucero et al., Cell Mol. Life. Sci., 2006 October; 63 (19-20):2304-16). LOXL1 is an extracellular enzyme associated with elastin fibers (Noblesse et al., J. Invest. Dermatol., 2004 March; 122 (3):621-30.). LOXL1 is expressed in the epidermis and dermis of a skin equivalent and in human skin LOXL1 is essential for elastic fiber formation and maintenance of elastic fibers homeostasis. LOXL1 knock-out mice have a connective tissue phenotype characterized by pelvic laxity in female animals and enlarged pulmonary air spaces that result from decreased elastin content (Liu et al., Nat. Genet., 2004 February; 36(2):178-82). Ultrastructural analysis shows poorly developed, fragmented and discontinuous elastic fibers in lung and skin In addition, mice lacking LOXL1 do not deposit normal elastic fibers in the postpartum uterus and develop loose skin and vascular abnormality with concomitant tropoelastin accumulation. Recent studies indicate that the LOXL1 mRNA level is reduced in adult skin fibroblasts compared with fibroblasts from children (Genizo et al., Exp. Dermatol., 2006 August; 15 (8):574-81.).
U.S. Patent Pub. No. 2005/0188427, the disclosure of which is hereby incorporated by reference, discloses a method of treating a subject having a condition associated with a loss of elastic fibers, such as loose or wrinkly skin, comprising administering to the subject a therapeutically effective amount of a LOXL1 enhancer. The LOXL1 enhancers are said to be LOXL1 polypeptides or active fragments thereof, or a nucleic acid encoding a LOXL1 polypeptide or active fragment thereof. The LOXL1 enhancers are also said to include small molecules or other therapeutic compounds identified by the screening method disclosed in that publication. There is no disclosure in U.S. Patent Pub. No. 2005/0188427 of the use of amino acids, other than in peptide form, to enhance LOXL1 expression.
Amino acids have become increasingly important constituents of cosmetics. For example, various natural amino acids have been incorporated into cosmetics as building blocks for collagen and elastin synthesis, for moisture retention, enhancing the skin barrier, reduction in sebaceous gland activity, and other functional properties. However, the use of non-natural, non-proteogenic amino acids has received little attention in the cosmetic industry. To date, the use of non-natural amino acids has been limited, for the most part, to imparting hydrolytic stability to functional peptides. Non-proteogenic aminoacids, by definition, do not become incorporated into proteins during new protein synthesis, and therefore, it would not be predicted that topical application of non-proteogenic aminoacids would lead to new protein synthesis in the skin and to skin rejuvenation benefits. The intrinsic functionality of non-natural, non-proteogenic amino acids has been largely ignored. The ability of non-natural, non-proteogenic amino acids to enhance LOXL-1 and modulate other pathways implicated in skin aging is heretofore unknown.
It is therefore an object of the invention to provide new cosmetic compositions and methods for enhancing LOXL-1 production in the skin using non-natural, non-proteogenic amino acids. It is a further object of the invention to provide cosmetic compositions and methods for improving the appearance of skin, including treating, reversing, and/or preventing signs of aging, such as skin wrinkles, using non-natural, non-proteogenic amino acids.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.